Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults

NCT03135028 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: GS-US-429-4104
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 6

Brief Summary

The primary objective of this study is to evaluate the safety and tolerability of entospletinib (ENTO) monotherapy and in combination with chemotherapy in Japanese participants.

Conditions

Hematologic Malignancy; Acute Myeloid Leukemia

Keywords

Relapsed or Refractory Hematologic Malignancy; Previously untreated AML

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT)

  Occurrence of any of the following toxicities, attributable to ENTO, during Cycle 1 was considered DLT: * Grade 4 non-hematologic toxicity except alopecia, nausea, and vomiting controllable with anti-emetic therapy, line associated venous thrombosis, infection-related toxicities such as fever/sepsis, and fatigue. * In participants without bone marrow evidence of hematologic malignancy, hematologic toxicity defined as failure to recover absolute neutrophil count (ANC \> 500/μL) or platelet count (\>25000/μL) within 28 days * Grade 4, clinically significant, electrolyte abnormalities that were not correctable within 24 hours * Liver function test abnormalities that did not resolve to Grade 2 within 10 days * Infection that resulted from unexpectedly complicated prolonged myelosuppression * Toxicities that required temporary interruption of treatment and did not resolve to Grade 2 within 10 days or ENTO was suspended or dose reduced for a period of more than 10 days.

  Cycle 1 (28-day cycle)

Secondary Outcomes (2)

• Percentage of Participants With AEs and Laboratory Abnormalities Not Defined as DLT

  Day 1 Up to 30 days after permanent discontinuation of study treatment (maximum approximately 80 weeks)

• Plasma Concentration of ENTO

  Cycle 1 (28-days cycle) Day 8 at 0 (predose), 1, 2, 3, 4, 6, 8, and 12 hours postdose

Study Arms (2)

ENTO monotherapy (Group A)

EXPERIMENTAL

Participants with relapsed or refractory hematologic malignancies will receive ENTO twice daily of every 28-day cycle until participants meet treatment discontinuation criteria or do not experience clinical benefit.

Drug: Entospletinib

ENTO + cytarabine + daunorubicin (Group B)

EXPERIMENTAL

Lead-in (Cycle 0): Participants with previously untreated AML will receive ENTO twice daily for 14 days. Induction (Up to 2 cycles): ENTO in combination with daunorubicin and cytarabine for up to two 28-day cycles. Post-remission chemotherapy (at least 2 cycles, up to 4 cycles): Some participants (who have achieved complete remission \[CR\] or morphologic complete remission with incomplete blood count recovery \[CRi\] and do not require or cannot proceed to allogeneic stem cell transplantation \[SCT\] and participants who are awaiting a donor or transitioning to allogeneic SCT per investigator discretion) will have the option to receive post-remission chemotherapy with ENTO twice daily in combination with high-dose cytarabine (Hi-DAC) for up to four 28-day cycles.

Drug: Entospletinib; Drug: Daunorubicin; Drug: Cytarabine

Interventions

Entospletinib DRUG

400 mg (2 × 200 mg tablets) orally twice daily

Also known as: GS-9973, ENTO

ENTO + cytarabine + daunorubicin (Group B); ENTO monotherapy (Group A)

Daunorubicin DRUG

60 mg/m\^2 administered intravenously daily on Days 1 to 3 of each 28-day induction cycle

ENTO + cytarabine + daunorubicin (Group B)

Cytarabine DRUG

100 mg/m\^2 intravenous administration twice daily on Days 1 to 7 of each 28-day induction cycle Hi-DAC: 3 g/m\^2 IV administration twice daily on days 1, 3, and 5 (≤ 60 years of age) or 1 g/m\^2 IV administration once daily on Days 1 to 5 (\> 60 years of age) of each 28-day post-remission cycle

ENTO + cytarabine + daunorubicin (Group B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ENTO monotherapy (Group A): relapsed or refractory hematologic malignancies by World Health Organisation (WHO) criteria and who are not eligible to receive standard of care
• ENTO + cytarabine + daunorubicin (Group B): previously untreated AML by WHO criteria, who are deemed fit for cytarabine and daunorubicin (7+3) induction chemotherapy and are able to undergo up to 2 cycles of induction chemotherapy, as determined by the treating physician
• Must have been born in Japan and must not have lived outside of Japan for a period \> 1 year in the 5 years prior to Day 1 of study treatment
• Must be able to confirm the Japanese origin of their maternal and paternal ancestry

You may not qualify if:

• Known active central nervous system or leptomeningeal leukemic involvement
• Ongoing liver injury, or known infection with chronic active hepatitis C virus (HCV) or chronic active hepatitis B virus (HBV)

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (6)

University of Fukui Hospital

Fukui, 910-1193, Japan

Location

Kyushu University Hospital

Fukuoka, 812-8582, Japan

Location

Tokai University Hospital

Kanagawa, 259-1193, Japan

Location

Tohoku University Hospital

Miyagi, 980-8574, Japan

Location

Kindai University Hospital

Ōsaka, 589-8511, Japan

Location

NTT Medical Center Tokyo

Tokyo, 141-8625, Japan

Location

MeSH Terms

Conditions

Hematologic Neoplasms; Leukemia, Myeloid, Acute; Recurrence

Interventions

6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; Daunorubicin; Cytarabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

The study was terminated early due to sponsor's decision based on the results from the Phase 1b/2 Study GS-US-339-1559 (NCT02343939) in participants with Acute Myeloid Leukemia and reorganization of the drug development portfolio.

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2017
• First Posted: May 1, 2017
• Study Start: May 19, 2017
• Primary Completion: February 26, 2019
• Study Completion: February 26, 2019
• Last Updated: March 6, 2020
• Results First Posted: March 6, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

JP (6)